Ofatumumab for B Cell Depletion Therapy in ANCA-Associated Vasculitis: Asingle-Centre

Ofatumumab for B cell depletion therapy in ANCA-associated vasculitis: asingle-centre case series

Stephen P McAdoo1,2, Rachna Bedi1, Ruth Tarzi3, Megan Griffith1,2, Charles D Pusey1,2,*, Tom Cairns1,*

1Vasculitis Centre, Imperial College Healthcare NHS Trust, London UK

2Renal and Vascular Inflammation Section, Imperial College London, London UK

*Charles D Pusey andTom Cairns equally contributed to this study.

Corresponding Author: Stephen P McAdoo, Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Email:

Running Title: Ofatumumab in AAV

Abstract

Objectives:B cell depletion is an effective treatment strategy in ANCA-associated vasculitis (AAV). Ofatumumab is a fully humanised anti-CD20 monoclonal antibody that has shown efficacy in the treatment of haematological malignancy and rheumatoid arthritis. The use of ofatumumab in the treatment of AAV has not previously been reported.

Methods: A case series of eight patients who received ofatumumab, in conjunction with low-dose cyclophosphamide and oral steroids, in the treatment of AAV.

Results:Eight patients received ofatumumab: seven for remission-induction in active disease (three relapsing; fourwith new disease) and one for remission-maintenance. B cell depletion was achieved in all patients by one month, and sustained until six months at least. All patients with active disease achieved clinical remission (BVAS of zero, or BVAS≤5 if all scores due to persistent urinary abnormalities in the presence of stable or improving renal function) by three months. This was associated with rapid fall in ANCA titres, reduced inflammatory responses, and improvements in renal function. At 12 months, three patients had repopulated B cells associated with recurrence of circulating ANCA, although no patients experienced major clinical relapse in the first 24 months. No unexpected safety signals were observed.

Conclusion:Treatment with ofatumumab resulted in similar serological and clinical responses to previous cohorts treated at our centre with a comparable corticosteroid, cyclophosphamide and rituximab-based regimen. Ofatumumab should be considered an alternative B cell depleting agent in patients who are intolerant of, or unresponsive to, rituximab.

Key words:ANCA; vasculitis; B cells;biological therapies; microscopic polyangiitis; granulomatosis with polyangiitis

Key Message:Ofatumumab is a potential alternative to rituximab for B cell depletion therapy in ANCA-associated vasculitis.

INTRODUCTION

Targeted B cell depletion has emerged as an effective treatment strategy in ANCA-associated vasculitis (AAV), both as remission-induction and remission-maintenance therapy(1-3). All reported series and trials using this approach have employed rituximab, a murine chimeric monoclonal antibody directed against the transmembrane calcium channel CD20,whichresults in predominantly antibody-dependent cellular cytotoxicity (ADCC)-mediated depletion of circulating B lymphocytes expressing this molecule.

Ofatumumab is a fullyhumanised monoclonal antibody directed against a distinct extracellular epitope of CD20, which has slower dissociation kinetics compared to rituximab, and whichhas been shown to be a more potent activator of complement-dependent cytotoxicity (CDC) in vitro(4). It is licensed for use in haematological malignancies, where it has shown biological activity in rituximab-resistant disease(5, 6). Notably, ofatumumab has also shown efficacy in rituximab-resistant cases of paediatric nephrotic syndrome(7), and has demonstrated biological activity in rheumatoid arthritis(8-10).

Here, we report our preliminaryexperience using ofatumumab for the treatment of AAV. This was based on experience of ofatumumab use in patients with lupus nephritis who demonstrated anaphylactic reactions to rituximab, and was initially used in a patient with AAV who had similarly demonstrated an anaphylactic reaction to rituximab. This approach was subsequently extended to include rituximab-naïve patients, based on our positive initial experience. Our treatment regimen using ofatumumab was based on our previously published protocol using rituximab in conjunction with low-dose pulsed intravenous cyclophosphamide and reduced steroid dose(11). This regimen, which has been standard of care for AAV with renal involvement at our centre since 2006, is associated with low cumulative exposure to cyclophosphamide and steroids, and prolonged disease-free remission. In the present study, rituximab was substituted by ofatumumab at the initiation of remission-induction therapy, and we report two year outcomes.

METHODS

This is a case series of eight patients treated between November 2012 and July 2013 at our centre, who received ofatumumab as a component of their treatment regimen for AAV. Ofatumumab was initially used at our centre on compassionate grounds for patients who were intolerant to rituximab due to anaphylaxis, but for whom anti-CD20 treatment was deemed appropriate (both in lupus nephritis and AAV; the lupus cohort will be reported separately). Following our positive initial experience in these patients, rituximab-naivepatients with AAV were also treated. Ofatumumab use was off-label,based on evidence supporting the use of anti-CD20 therapy in AAV at that time, andpredated the licensing of rituximab for this indication in 2013 (when use of the latter agent was similarly off-label)Use of ofatumumab was guided by expert opinion at our centre andapproved by the Glomerulonephritis Protocol and Research Group at Imperial College Healthcare NHS Trust..

The treatment protocol was based on our previously reported regimen using low-dose pulsed intravenous cyclophosphamide and steroids, in conjunction with anti-CD20 treatment(11), which has been standard of care at our centre since 2006. Herein, rituximab 2x1g was substituted with ofatumumab 2x700mg administered at Day 0 and Day 14.The additional components of the protocol included intravenous cyclophosphamide 10mg/kg administered at Day 0 and 14 (maximum 750mg each) and then every 14 days for a further four doses (maximum 500mg each). Oral prednisolone 1mg/kg was started at Day 0 (maximum 60mg) and reduced sequentially to achieve a dose of 10mg by Week 13. Further steroid weaning was at discretion of the treating physician. Where patients were treated for relapsing disease or for remission-maintenance, or had received pulsed intravenous methylprednisolone before referral to our centre, modified doses of either steroids or cyclophosphamide may have been used. Therapeutic plasma exchange was offered for patients who presented with dialysis-dependent renal failure. In these cases, administration of the first dose of ofatumumab was delayed until completion of plasma exchange. Maintenance therapy commenced at three months, after completion of cytotoxic therapy, or earlier in those who received modified doses of cyclophosphamide. First-line maintenance was with azathioprine; mycophenolate mofetil was used in those who were intolerant. Patients received prophylactic co-trimoxazole for three months, proton pump inhibitors and bone protection with calcium/D3. Patients from high-risk groups were also given prophylaxis against tuberculosis with isoniazid and pyridoxine.

Patients were regularly assessed by both clinical and laboratory measures. Disease activity was scored using version 3 of the Birmingham Vasculitis Activity Score (BVAS)(12). Laboratory assessments included monitoring of B cell count, ANCA titre, serum CRP, and renal function as determined by serum creatinine measurements.

Informed consent was provided prior to initiation of therapy in all cases. In accordance with the UK National Health Service Research Ethics Committee guidelines, ethics approval was not required for this report, as all treatment decisions were made prior to this evaluation, and were part of a formal change in our standard-care regimen

RESULTS

Individual patient characteristics and details of their treatment are summarised in Table 1. The demographic features of this cohort are in keeping with that of the population of patients with vasculitis seen at centre. The cohort included a mixture of AAV disease phenotypes, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Five of the six patients with renal involvement had confirmatory renal biopsies demonstrating necrotizing or crescentic glomerulonephritis. Two patients were ANCA-negative; of these, one had a renal biopsy confirming necrotizing glomerulonephritis consistent with small-vessel vasculitis (Case 5). The second ANCA-negative patient had an established diagnosis of EGPA based on prior presentation with adult-onset asthma, sinusitis, biopsy-proven granulomatous panniculitis and peripheral blood eosinophilia (Case 3). Two patients presented with dialysis-dependent renal failure and received plasma exchange in addition to medical therapy with anti-CD20, cyclophosphamide and corticosteroids.Three patients were treated for relapsing disease, one for maintenance of remission in EGPA (in response to rising ANCA titres and eosinophilia without clinical manifestations), and four patients for new disease presentations. Of the two patients who had previously received anti-CD20, one had demonstrated an anaphylactic infusion reaction to rituximab (Case 1) and on this basis was treated with ofatumumab.

All patients experienced B cell depletion by one month, as defined by an absolute B cell count of <5cells/μl (Figure 1A). B cell depletion was sustained until at least 6 months in all patients. This was associated with rapid reduction in ANCA titres (Figure 1B). All patients with active disease achieved clinical remission by three months, as defined by BVAS of zero or BVAS ≤5 if all scores were due to persistent haematuria or proteinuria in the presence of stable or improving renal function as measured by serum creatinine (Figure 1C). This was associated with reduced acute phase response (Figure 1D), and the ability to taper corticosteroid treatment (Figure 1E). The median total dose of cyclophosphamide administered was 3.05g. In those patients with renal involvement (n=6), there was improvement in renal function in five cases (Figure 1F).One patient who presented with dialysis-dependent renal failure and 50% interstitial fibrosis and tubular atrophy on renal biopsy, did not recover independent renal function (Case 8).His other disease manifestations did, however, resolve (BVAS 0 at 3 months) and he remained in stable remission allowing successful renal transplantation at 21 months. This was with alemutuzumab-based induction and tacrolimus monotherapy for immunosuppression (13). Accordingly, he remains lymphocyte deplete, with no clinical features of vasculitis and no evidence of disease recurrence on allograft surveillance biopsy.

At 12 months, three patients had repopulated B cells (absolute count >20cells/μl), in all cases associated with recurrence of circulating ANCA (Cases 2, 6, and 7), although no patients experienced clinical relapse in the first year. At 24 months, a further patient reconstituted B cells with weakly positive ANCA, though without clinical features of relapse (Case 1). In those patients who reconstituted B cells over the two year follow-up period, the median time to reconstitution was 11.8 months. After two years follow-up, one ANCA-negative patient with EGPA (Case 3) experienced two minor relapses, in the absence of B cell reconstitution, at 15 and 21 months, which were treated with oral corticosteroids only.

We did not detect any unexpected safety signals: one patient experienced a minor infusion reaction to ofatumumab; three urinary tract infections, one upper respiratory tract infection and one lower respiratory tract infection occurred in three patients; one patient had a transient episode of neutropenia not associated with infection. There were no atypical or opportunistic infections and we did not detect any episodes of hypogammaglobulinaemia or hepatitis reactivation.

CONCLUSION

This is the first reported use of ofatumumab in AAV, and our preliminary data suggest that this agent results in similar serological and clinical responses to previous cohorts treated with a comparable corticosteroid, cyclophosphamide and rituximab-based regimen at our centre(11), with complete B cell-depletion within one month, sustained in half of patients at 24 months, and associated with prolonged relapse-free survival.

Our experience suggests that ofatumumab warrants further investigation as an alternative B cell depleting agent in AAV. This may be of particular use in patients who are intolerant of rituximab due toinfusion-related reactions. Indeed, there is a previous case report of successful ofatumumab use in a patient with systemic lupus erythematosus who developed anaphylaxis following rituximab infusion(14). Notably, human anti-chimeric antibodies (HACA)have been implicated in the generationof infusion reactions following repeated rituximab exposure (with reported HACA frequencies of up to 11% in some cohorts(15)) though their clinical significance is not fully understood. As a fully humanized antibody, ofatumumab may avoid immunogenic anti-drug reactions(9), which may have additional benefits both for tolerability and efficacy after repeated exposure. Future studies might also explore potential cost benefits of alternative B cell depleting agents; the cost per course in the UK using our protocols equates to £2548 (2x700mg ofatumumab) versus £3492 (2x1g rituximab).

Our report has obvious limitations; the cases are smallin number and heterogeneous, and the series is uncontrolled. Several patients received cyclophosphamide in addition to ofatumumab, which may have affected both B cell survival and clinical response, though it is notable that complete B cell depletion was observed in both patients who did not receive concurrent cyclophosphamide. In addition, the median dose of cyclophosphamide administered (3.05g) was significantly lower than that reported in published studies using cyclophosphamide alone as remission-induction therapy (for example, 8.2g and 15.9g in the pulsed-intravenous and daily-oral groups, respectively, in the CYCLOPS study(16)). In addition, the inclusion of low-dose cyclophosphamide treatment for patients with severe renal disease is consistent with the use of rituximab in the RITUXVAS study(2). Notably, the rapidity, depth and duration of B cell depletion that we observed in our cohort is greater than that seen in the published studies using cyclophosphamide alone (for example, fewer than 10% of patients in the control limbs of the RITUVAS and RAVE studies achieved B cell depletion within the first month (17, 18)). Collectively, these observations suggest that a significant proportion of the B cell depleting and therapeutic effect seen in our cohort is due to the activity of ofatumumab. We acknowledge, however, that the synergistic effect of co-administration of anti-CD20 with low-dose cyclophosphamide is not fully understood and requires further investigation.

Finally, we have not examined the utility of ofatumumab in rituximab-resistant disease, for which there is evidence in the treatment of paediatric nephrotic syndrome and haematological malignancy, potentially due to differences in drug epitope specificity, pharmacokinetics, or the potential to avoid induction of HACA. Larger studies, including randomised controlled trials, are clearly needed to address these questions and to more precisely define the role of this and other emerging anti-B cell therapies in AAV. Pending these studies, this series provides a potential dosing regimen and preliminary evidence that ofatumumab may be a useful alternative agent in the treatment of AAV.

ACKNOWLEDGMENTS

The data reported here were presented in abstract form at the American Society of Nephrology Renal Week meeting in Philadelphia, PA, in November 2014, and at the 17th International Vasculitis and ANCA Workshop in London UK, in May 2015.SPM is in receipt of a UK MRC Clinical Research Training Fellowship and a NIHR Academic Clinical Lectureship.

The NIHR Imperial Biomedical Research Centre supports all clinical research undertaken in our department. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure Statement: R.T. has been employed as a clinical development director by GlaxoSmithKline since April 2014. However her involvement in this project was in an academic capacity prior to joining GSK. The views contained herein are the views of the authors and not necessarily those of GlaxoSmithKline. All other authors have declared no conflicts of interest.

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